ANALYSE DE LA ZONE DE RECOMBINAISON AU COURS D'UNE PERSISTANCE HEREDITAIRE DE L'HEMOGLOBINE FOETALE AVEC REARRANGEMENT DES GENES FOETAUX DE TYPE G(γ)-G(γ)-A(γ)

An increased synthesis of fetal hemoglobin in adult life is a common feature of the genetically determined severe disorders like β thalassemia and sickle cell anemia. A continued synthesis of fetal hemoglobin in adults is also characteristic of clinical or subclinical syndromes like respectively δβ thalassemia or hereditary persistence of fetal hemoglobin (HPFH). These disorders are highly heterogeneous with respect to their molecular defects as well as to the composition of Hb F. We report here a novel case of hereditary persistence of fetal hemoglobin in heterozygous state discovered by chance, in a young perfectly healthy french man. The γ chain of his fetal hemoglobin was almost entirely composed of G(γ) chains. Molecular analysis of the DNA revealed the existence of triplicated γ genes on one chromosome with the genotype arrangement of G(γ)-G(γ)-A(γ). A polymorphic Xmn I restriction site (at position - 158 5' to the cap site) was present in 5' of both of these G(γ) genes. The presence of this site in front of G(γ) gene had previously been shown to be associated both with high G(γ) phenotype constitutively and also with high fetal hemoglobin level only in case of anemic stress. In the absence of any anemic stress in this individual, the constitutive increase of both fetal hemoglobin and G(γ) chains could be due to the presence of a chromosome with triplicated arrangement of γ genes. The classical triplication(G(γ)-A(γ)-G(γ)-A(γ)) does not result in HPFH phenotype. Hence the novel rearrangement involved in G(γ)-G(γ)-A(γ) genotype is considered to be responsible for the high G(γ) HPFH phenotype observed. Such rearrangement has been shown to be due to a cross over event which has been localised between nucleotides -1032 and -158 5' to the cap site of G(γ) gene. A critical comparison of the data in the literature with ours strongly suggests that the DNA sequences modified in the rearrangement in this region might be of regulatory importance in the fetal hemoglobin expression.